Iron-deficiency anemia has been described as one of the most common--possibly the most common--pathological conditions among humans when viewed on a global basis. Also in modern farm-breeding of pigs and other domestic animals iron-deficiency anemia is a problem unless suitable prophylactic measures are taken.
Although iron-deficiency anemia can often be prevented or cured by oral administration of iron-containing preparations, it is in many cases preferred to use parenterally administrable iron preparations to avoid variations in bioavailability of oral administrations and to ensure effective administration.
Therefore, iron-containing preparations for parenteral use, that means subcutaneous, intramuscular or intravenous administration, have for many years been at the disposal of the veterinary or human medical practitioner.
Although various iron-containing substances have been used or suggested as components in parenterally injectable preparations against iron-deficiency anemia, the most common preparations accepted today are such which comprise a combined product of ferric oxyhydroxide (or ferric hydroxide) in association with dextran. Dextran is a polymeric carbohydrate produced by the microorganisms Leuconostoc mesenteroides.
An iron-containing preparation for parenteral injection should obviously satisfy several requirements including ready availability of the iron for haemoglobin synthesis, absence of local or general side-effects and stability on storage enabling a satisfactory shelf-life at ambient temperature.
Iron-dextran preparations for the treatment of anemia have been marketed for decades, and many variations in the manufacturing process and in the selection of starting materials have been suggested with a view to improving the stability of such preparations and to decrease the amount of side effects obtained at their administration.
As examples of patents dealing with these problems the following may be cited:
U.S. Pat. No. 2,885,393 (1959) describes a basical process of producing an iron-dextran complex in which the average molecular weight of the dextran is 30,000 to 80,000 Daltons or lower. The suitability of these complexes for human therapy does not appear from this patent specification.
U.S. Pat. No. Re. 24,642 (1959) comprises a detailed explanation of the requirements to an iron solution intended for intramuscular injection, incorporated herein by reference. The patent deals with a substantially nonionic complex of ferric hydroxide with a dextran having an average intrinsic viscosity at 25.degree. C. of about 0.025 to about 0.25, as well as a process for preparing such a complex by contacting a dextran as described with ferric hydroxide formed in situ by reaction between a ferric salt and an alkali base. No information as to the desired molecular weight of the dextran is given, and no chemical modification of the dextran, apart from a partial depolymerisation, is suggested.
U.S. Pat. No. 3,093,545 (1963). This patent discloses some details such as temperatures and pH-values in an improved method of preparing a product apparently very similar to the one prepared in the last mentioned above patent.
GB 1,200,902 (1970) teaches that in contrast to preparing the ferric hydroxide in situ it is advantageous to preform the ferric hydroxide under controlled conditions since such ferric hydroxide will readily form complexes with dextrans. It is stated that not only partially depolymerised dextran having a weight average molecular weight in the range of for example 500-50,000 Daltons, preferably in the range 1,000-10,000 Daltons, but also modified forms or derivatives of dextran such as hydrogenated dextrans or oxidised dextrans or alkali treated dextrans come into consideration as theoretical possibilities. However, the only dextrans specifically mentioned are oxidized dextrans having an average molecular weight of 3,000 and 5,000 Daltons, resp. The ferric hydroxide is prepared before contact with the dextran. This means that the resulting product consists of ferric oxyhydroxide on which the dextran forms a coating in contrast to the more homogeneous products formed by precipitating the ferric hydroxide in situ, that means in the presence of the dextran.
DK 117,730 (1970) deals with a process in which hydrogenated dextran having a molecular weight between 2,000 and 10,000 Daltons is reacted with ferric hydroxide in aqueous medium. The average molecular weight of the dextran used in the embodiment examples is not indicated. However, the intrinsic viscosity is stated as approximately 0,05 which could correspond to an average molecular weight of approximately 5,000 Daltons.
DK 122,398 (1972) also discloses the use of hydrogenated dextran for preparing complex compounds with ferric hydroxide, and it is explained that a substantial lower toxicity is obtained than when non-hydrogenated dextran is used. The subject of the patent is a process in which moist ferric hydroxide is mixed with dry hydrogenated dextran, and after optional addition of citric acid or citrate the mixture is heated and purified.
U.S. Pat. No. 3,697,502 (1972) discloses a process for producing an iron-dextran preparation in which citric acid is added to the dextran and a simultaneous addition of alkali metal hydroxide solution and ferric chloride solution is made. The average molecular weight of the dextran is between 3,000 and 20,000 Daltons. The dextran used in the embodiment examples has a molecular weight of 7,000 and 10,000 Daltons, resp.
DK 129,353 (1974) is directed on an analogy process for producing a ferric hydroxide-dextran derivative at an average molecular weight of the dextran of at the most 50,000 Daltons, and the terminal groups of the polymer chains thereof have been modified to convert the terminal reducing anhydroglucose unit into a corresponding carboxylic acid group. Although the limits indicated for molecular weight of the dextran are very broad, viz. from 500 to 50,000 Daltons, preferably from 1,000 to 10,000 Daltons, the only exemplified dextran has an average molecular weight of 5,000 Daltons.
DK 129,942 (1974) has similarity to the above last mentioned DK patent and deals with the manufacture of ferric hydroxide complexes with dextran hepton acid or dextrine hepton acid. The hepton acids are prepared by hydrolyzing the corresponding cyanhydrids.
U.S. Pat. Nos. 4,827,945 (1989) and 5,102,652 (1992) both deal with superparamagnetic metal oxides such as iron oxides coated with or associated with polymeric materials such as dextran. The polymer is contacted with a mixture of the metal oxides in two different oxidation stages to produce a superparamagnetic combined product which is afterwards oxidized to transform all the metal oxide into the highest of said oxidation steps. The product is especially useful as contrast agent in magnetic resonance imaging in medical diagnosis. However, it is also mentioned that they can be used for treatment of iron-deficiency anemia. The molecular weight of the polymers, including carbohydrates such as dextran are preferably from 5,000 to 250,000 Daltons.
GB patent 1,076,219 describes the production of an iron preparation, wherein the ferric hydroxide is bound to a complexforming agent consisting of sorbitol, gluconic acid and a oligosaccharide in a certain proportion, where sorbitol is the dominating component. In one of the examples in the specification of the patent a hydrogenated dextran with an average molecular weight of about 1000 Daltons is used as oligosaccharide. From the process described for the production of this dextran it can be deduced that its contents of very low molecular weight components must be high. Even more important in connection with the present invention is, however, cf. the explanation below, that at the time of complexformation a high amount of hydrogenated monomer of dextran, i.e. sorbitol, is present.
In spite of the several attempts to improve iron-dextran preparations for treatment of anemia, as reflected in the above patents, the preparations prepared according to the state of the art have still some drawbacks.
This is a result of the fact that in some patients the preparations may cause delayed hypersensitivity, or severe anaphylactic side effects, resulting f.inst. in dyspnea, hypotension, shock and death. Also other toxic reactions might be observed.
Besides, several of the prior art preparations are not able to meet current requirements as to stability. Lacking stability may manifest itself as gelatination of the liquid or precipitation of iron hydroxide or oxyhydroxide.